Development and application of QM/MM calculations for fragment-based drug design
Lead Research Organisation:
University of Essex
Department Name: Biological Sciences
Abstract
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Technical Summary
Fragment-based drug design, FBDD, is a highly promising novel approach for
identifying lead compounds in a drug development programme10. It therefore lies
firmly within one of the 10 MRC-identified health research opportunities for focusing
strategic research, namely ?Development of new interventions?. FBDD offers efficient
screening of chemical space so that higher hit rates are obtained in the initial phases
and through careful attention to molecular properties the resulting drug candidates
should have less chance of failure later in the process. However, FBDD also poses
difficult biophysical and structural problems that need to be addressed, hence the
strategic need for this proposal. The academic partner has current BBSRC funding to
develop quantum mechanics (QM) based QM/MM methods that include molecular
mechanics (MM) polarization. He has plans for other significant improvements to
correctly address the steric repulsion between drug and enzyme using exponential
repulsion (which is essential for success in crystal structure prediction11) rather than
the computationally expedient r-12 repulsion. The industrial partner has a strong
development interest in FBDD and is interested in using QM/MM to address the
structural demands of FBDD since current docking methods are unreliable and the
interpretation of X-ray structures of bound fragments can be ambiguous. The
interchange enabled by this programme, will not only result in the development of
new tools to underpin basic FBDD research, but also offers the potential to impact
industrial and academic scientists in both institutions. Specific research goals include
(i) a thorough survey of the usefulness of QM/MM in virtual screening. (ii) An analysis
of the best way in which QM/MM with MM polarization can be used in virtual
screening. (iii) An investigation of the use of realistic repulsion in virtual screening.
(iv) An investigation in the use of QM/MM, in combination with the proposed
improvements, in interpreting ambiguous X-ray crystal structures. The applicants
have shared research goals as the industrial partner is interested in being able to
apply efficient software to FBDD while the academic partner is interested in
developing relevant computational methods that can be applied to the problem of
improving the quality of life.
9. Maurer, RI; Blower, PJ; Dilworth, JR; Reynolds, CA; Zheng, YF; Mullen, GED
Studies on the mechanism of hypoxic selectivity in copper bis(thiosemicarbazone)
radiopharmaceuticals. J. Med. Chem. 2002, 45, 1420-1431.
10. Congreve, M; Chessari, G; Tisi, D; Woodhead, AJ. Recent developments in
fragment-based drug discovery. J. Med. Chem 2008, 51, 3661-3680.
5
11. Misquitta, AJ; Welch, GWA; Stone, AJ; Price, S. L. A first principles prediction of
the crystal structure of C6Br2ClFH2. Chem. Phys. Lett. 2008, 456, 105-109.
12. Jorgensen, WL Special issue on polarization. J. Chem. Theory Comput. 2007, 3,
1877.
13. Mura, ME; Knowles, PJ; Reynolds, CA Accurate numerical determination of Kohn-
Sham potentials from electronic densities .1. Two-electron systems. J. Chem. Phys.
1997, 106, 9659-9667.
identifying lead compounds in a drug development programme10. It therefore lies
firmly within one of the 10 MRC-identified health research opportunities for focusing
strategic research, namely ?Development of new interventions?. FBDD offers efficient
screening of chemical space so that higher hit rates are obtained in the initial phases
and through careful attention to molecular properties the resulting drug candidates
should have less chance of failure later in the process. However, FBDD also poses
difficult biophysical and structural problems that need to be addressed, hence the
strategic need for this proposal. The academic partner has current BBSRC funding to
develop quantum mechanics (QM) based QM/MM methods that include molecular
mechanics (MM) polarization. He has plans for other significant improvements to
correctly address the steric repulsion between drug and enzyme using exponential
repulsion (which is essential for success in crystal structure prediction11) rather than
the computationally expedient r-12 repulsion. The industrial partner has a strong
development interest in FBDD and is interested in using QM/MM to address the
structural demands of FBDD since current docking methods are unreliable and the
interpretation of X-ray structures of bound fragments can be ambiguous. The
interchange enabled by this programme, will not only result in the development of
new tools to underpin basic FBDD research, but also offers the potential to impact
industrial and academic scientists in both institutions. Specific research goals include
(i) a thorough survey of the usefulness of QM/MM in virtual screening. (ii) An analysis
of the best way in which QM/MM with MM polarization can be used in virtual
screening. (iii) An investigation of the use of realistic repulsion in virtual screening.
(iv) An investigation in the use of QM/MM, in combination with the proposed
improvements, in interpreting ambiguous X-ray crystal structures. The applicants
have shared research goals as the industrial partner is interested in being able to
apply efficient software to FBDD while the academic partner is interested in
developing relevant computational methods that can be applied to the problem of
improving the quality of life.
9. Maurer, RI; Blower, PJ; Dilworth, JR; Reynolds, CA; Zheng, YF; Mullen, GED
Studies on the mechanism of hypoxic selectivity in copper bis(thiosemicarbazone)
radiopharmaceuticals. J. Med. Chem. 2002, 45, 1420-1431.
10. Congreve, M; Chessari, G; Tisi, D; Woodhead, AJ. Recent developments in
fragment-based drug discovery. J. Med. Chem 2008, 51, 3661-3680.
5
11. Misquitta, AJ; Welch, GWA; Stone, AJ; Price, S. L. A first principles prediction of
the crystal structure of C6Br2ClFH2. Chem. Phys. Lett. 2008, 456, 105-109.
12. Jorgensen, WL Special issue on polarization. J. Chem. Theory Comput. 2007, 3,
1877.
13. Mura, ME; Knowles, PJ; Reynolds, CA Accurate numerical determination of Kohn-
Sham potentials from electronic densities .1. Two-electron systems. J. Chem. Phys.
1997, 106, 9659-9667.
